title: Targeting cancer with a bi-functional peptide: in vitro and in vivo results.
abstract: BACKGROUND
  Current therapies to treat cancer, although successful for some patients, have significant side-effects and a high number of patients have disease that is either non-responsive or which develops resistance. Our goal was to design a small peptide that possesses similar functions to an antibody drug conjugate with regard to targeting and killing cancer cells, but that overcomes size restrictions.
  
  
  METHODS
  We designed a novel cancer-specific killer peptide created by fusion of the toxic peptide (KLAKLAK)2 with the cancer recognition peptide LTVSPWY.
  
  
  RESULTS
  This bi-functional peptide showed toxicity to breast cancer, prostate cancer, and neuroblastoma cell lines. Only low toxicity to non-cancer cells, colon cancer, lung cancer, and lymphoma cell lines was observed. In vivo injections of the bi-functional peptide caused tumor growth retardation compared to mice treated with control peptides. The bi-functional peptide caused retardation of MDA-MB-435S tumors in vivo and increased survival to 80% at day 100 after tumor implantation, whereas all control animals died at day 70. Previous reports showed that the recognition moiety LTVSPWY targets the tumor-associated antigen HER2. Here we found that our new peptide TP-Tox also excerts toxic effects on HER2-negative cell lines. Therefore, we searched for the molecular target of the bi-specific peptide using immunoprecipitation and mass spectrometry. Our data suggest a possible interaction with RAS GTPase-activating protein binding protein 1 (G3BP1).
  
  
  CONCLUSIONS
  We designed a bi-functional peptide of 23 amino acids and demonstrated its ability to bind and kill several cancer cell lines in vitro and to strongly increase survival in breast cancer bearing mice in vivo. This novel toxin could be used in future cancer therapies and warrants further pre-clinical and clinical exploration.
authors.affiliation: Department of Internal Medicine III, Center for Integrated Oncology, University Hospital Bonn, Bonn, Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: Meschenmoser
authors.forename: Young
authors.initials: Y
authors.lastname: Kim
authors.forename: Sebastian
authors.initials: S
authors.lastname: Franken
authors.forename: Michael
authors.initials: M
authors.lastname: Nowak
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Gerd
authors.initials: G
authors.lastname: Bendas
authors.forename: Matthias
authors.initials: M
authors.lastname: Wolfgarten
authors.forename: Davorka
authors.initials: D
authors.lastname: Messmer
authors.forename: Ingo G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D004705:Endocytosis; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides
keywords: G3BP1; Targeting cancer; peptide; toxin